Use of guanabenz or derivates thereof for the treatment of type i ifn-dependent pathologies

Abstract

The present invention relates to the use of Guanabenz or derivates thereof for the treatment of type I IFN-dependent pathologies. The inventors investigate here how pharmacological interference with the eIF2α-P pathway can be beneficial for the treatment of immune pathological conditions. Using both mouse and human DCs, as well as B cells, they show that GBZ prevents endosomal toll-like-receptor 9 (TLR9) activation by CpG ODN or DNA-Immunoglobulin complexes, as well as TLR3, TLR7 and RIG-I like receptors (RLR, RIG-I or MDA5), by RNAs or small compounds. In vivo, GBZ treatment protects mice from CpG-dependent cytokine shock and decreases anti-nucleic acid auto-antibodies production in the TMPD-induced systemic lupus erythematosus model. The present invention thus relates to a method of treating a type I IFN-dependent pathology in a subject comprising administering the subject with Guanabenz or a derivative thereof.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the use of Guanabenz or derivatives thereof for the treatment of type I IFN-dependent pathologies.BACKGROUND OF THE INVENTION[0002]Dendritic cells (DCs) are regulators of the immune response whose immune-modulating functions, like antigen presentation, are considerably enhanced after detection of cell damage-associated or pathogen-associated molecular patterns (DAMPs & PAMPs). Toll-like receptors (TLRs) have a major role in PAMPs recognition and most TLRs detect their ligand at the cell surface, except TLR3, TLR7, TLR8 and TLR9 that are found in endosomes. TLR7 and TLR9, whose ligands are respectively ssRNA and DNA with unmethylated cytosine-phosphate-guanine (CpG) motifs, are expressed in a restricted number of immune cells, like B cell or plasmacytoïd DC (pDC), which specializes in the production of type-I interferon (IFN). In a pathological context, improper stimulation of endocytic TLRs by self-nucleic acids drives a f...

AI Technical Summary

Benefits of technology

The patent text discusses a compound called Guanabenz and its effects on immune cells. The researchers found that Guanabenz prevents the activation of certain receptors in immune cells and reduces the production of inflammatory molecules. This compound could be useful in treating auto-inflammatory diseases and preventing the formation of lipogranulomas, a condition that causes pain and swelling. Overall, the researchers found that Guanabenz and its derivatives have a protective effect on immune cells and could be developed into a therapeutic drug.

Problems solved by technology

This phosphorylation inhibits the guanine nucleotide exchange factor eIF2B and results in reduced translation initiation and diminished production of newly synthesized proteins.

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